N-(4-Hydroxyphenyl)acetamide (acetaminophen, paracetamol, APAP) is a very widely used and effective pain relieving agent. It occupies a therapeutic niche between the highly efficacious opioid class and the non-steroidal anti-inflammatory drugs (NSAIDs, COX-1/COX-2). It lacks the typical side effects of the opioids (physical dependence, constipation, CNS) as well as the side effects associated with NSAIDs (gastrointestinal irritation, cardiovascular). Though lacking the efficacy of the opioids and the anti-inflammatory effects of NSAIDs, when used at recommended doses by appropriate subjects, acetaminophen would seem to be an almost side effect free pain relieving drug. The issue with acetaminophen is that, when used at high doses or in subjects with compromised liver function, it can cause liver damage. Furthermore, in conjunction with the high doses needed for pain relief, the potential toxicity also points to significant unmet medical need in terms of therapeutic index.
Even after over a century of use, there is no universally accepted mechanism. Mechanistic possibilities include interaction with the peroxidase site on the COX enzyme, action on the endocannabinoid system, indirect interaction with serotonergic pathways, action on TRP channels and indirect interaction with opioid pathways. Lack of certainty of acetaminophen's mechanism makes finding a safer alternative drug a challenge.
While the mechanism of action of acetaminophen remains unclear, the primary mechanism for its toxic effects is well understood. See, Scheme 1. At high doses, acetaminophen I undergoes oxidation to a reactive quinoneimine II which is able to react with tissue sulfhydryl groups (BioNuSH) to provide compound III with resulting cytotoxicity.

Thus, there is a need for compounds for treating pain, while avoiding the toxic effects of acetaminophen. The invention is directed to these and other important needs.